We have shown that alternating radiotherapy and chemotherapy is superior to either modality given alone with the same schedule and total dose in the solid tumor line 3924A in ACI rats. Cure rates greater than 50% have been obtained using alternate radiation and cyclophosphamide (CP). We have not been successful in obtaining cure rates of 100% within the limits of host toxicity and normal tissue tolerance, and marked changes in growth rates of these persisting tumors occur following treatment. Many studies have been conducted on the cross resistance and cross sensitivity of different cancer chemotherapeutic agents. Little information is available on either the cross sensitivity or cross resistance of radiotherapy with chemotherapy or the changes in therapeutic response following combined chemotherapy-radiotherapy. The tumor line 3924A is responsive to both radiation and CP. Another tumor line, H-4-II-E, is resistant to both treatment modalities. If resistance develops to either modality, it will also provide information on cross resistance or cross sensitivity to the other modality. One of the primary objectives of this study is to determine if growth rate changes in the tumor can be related to changes in the clonogenic potential and cytogenic characteristics of the treated tumor cells. Standard Q-banding and G-banding will be done on chromosome preparations in order to identify chromosomes involved in changes in chromosome numbers or in rearrangements. The aim of these studies therefore is to look for consistent and stable changes that can be correlated wth changes in growth and drug or radiation resistance or sensitivity. Soft agar techniques for testing changes in cloning efficiency of treated tumors will be carried out using the basic cell culture technique described by Hamburger and Salmon (1977). This study will begin to provide information on the possible development of cross resistance and cross sensitivity of alternating chemotherapy and radiotherapy during treatment. If we can demonstrate that the superiority of our alternate cyclophosphamide and radiation schedule in 3924A is related to subpopulations of tumor cells with differing sensitivities to each modality, it would have broad implications with regard to a better understanding of the development of therapeutic resistance in combined modality therapy.